Filling in the Gaps. Making Sense of Living with Temporomandibular Disorders: A Reflexive Thematic Analysis.

INTRODUCTION: Persistent, painful temporomandibular disorders (TMDs) are challenging to manage and usually require the active engagement of patients. To achieve this, it is necessary to understand the complex and multifactorial nature of persistent pain. Many dental professionals have little education about persistent pain and may prefer to offer structural management and advice. This research aims to explore how people understand their persistent TMD and how this understanding has been influenced by their treatment providers. METHODS: Twenty-one people were recruited to represent a diversity of experience with persistent TMD. Interviews followed a semistructured topic guide. Themes were constructed through reflexive thematic analysis to represent how people made sense of their symptoms and the messages that they had picked up through their treatment journey. RESULTS: Participants described examples of conflicting opinions and inconsistent management recommendations. They rarely recalled collaborative discussions about the nature and complexity of their symptoms and different options for treatment. This experience is represented by a single theme, "a medical merry-go-round." Subthemes of "a medical journey to nowhere-participants' frustrated attempts to find medical management that will end their pain" and "is it me?-participants' questioning their role in persisting pain" kept participants on the merry-go-round, while symptom resolution and participants' emerging development of a holistic understanding of their TMD pain provided exit points. Understanding pain holistically tended to be helpful and typically occurred despite rather than because of the advice given in routine treatment settings. CONCLUSION: Participants in this study had not typically found their pain management within dental and medical settings to have helped them to construct meaning and understand their experiences of painful TMD. However, understanding symptoms holistically was experienced as beneficial. This study suggests that improved communication and signposting within services for persistent TMD may be beneficial to patients with TMD pain. KNOWLEDGE TRANSFER STATEMENT: Results of this study confirm that being offered a series of anatomically based, singular-cause explanations for persisting pain symptoms had been experienced as unhelpful by the participants who had sought help for their TMD. Participants highlighted the importance of accurate and collaborative communication and of dental professionals explicitly adopting and communicating a biopsychosocial understanding of pain to their patients who have TMD. Results highlight that some people can struggle to manage persisting pain with minimal support. Signposting patients to appropriate services and resources may help them to understand more about the nature of persistent pain and methods of managing it.

Current insights into the role of citrullination in thrombosis.

Protein citrullination is a post-translational modification of arginine that controls a diverse array of cellular processes, including gene regulation, protein stability, and neutrophil extracellular trap (NET) formation. Histone citrullination promotes chromatin decondensation and NET formation, a pro-inflammatory form of cell death that is aberrantly increased in numerous immune disorders. This review will provide insights into NETosis and how this novel form of cell death contributes to inflammatory diseases, with a particular emphasis on its role in thrombosis. We will also discuss recent efforts to develop PAD-specific inhibitors.

In-person versus virtual administration of the American College of Rheumatology gold standard cognitive battery in systemic lupus erythematosus: Are they interchangeable?

OBJECTIVE: During the COVID-19 pandemic, many research studies were adapted, including our longitudinal study examining cognitive impairment (CI) in systemic lupus erythematosus (SLE). Cognitive testing was switched from in-person to virtual. This analysis aimed to determine if the administration method (in-person vs. virtual) of the ACR-neuropsychological battery (ACR-NB) affected participant cognitive performance and classification. METHODS: Data from our multi-visit, SLE CI study included demographic, clinical, and psychiatric characteristics, and the modified ACR-NB. Three analyses were undertaken for cognitive performance: (1) all visits, (2) non-CI group visits only and (3) intra-individual comparisons. A retrospective preferences questionnaire was given to participants who completed the ACR-NB both in-person and virtually. RESULTS: We analysed 328 SLE participants who had 801 visits (696 in-person and 105 virtual). Demographic, clinical, and psychiatric characteristics were comparable except for ethnicity, anxiety and disease-related damage. Across all three comparisons, six tests were consistently statistically significantly different. CI classification changed in 11/71 (15%) participants. 45% of participants preferred the virtual administration method and 33% preferred in-person. CONCLUSIONS: Of the 19 tests in the ACR-NB, we identified one or more problems with eight (42%) tests when moving from in-person to virtual administration. As the use of virtual cognitive testing will likely increase, these issues need to be addressed - potentially by validating a virtual version of the ACR-NB. Until then, caution must be taken when directly comparing virtual to in-person test results. If future studies use a mixed administration approach, this should be accounted for during analysis.

Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans.

Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.

The impact of lead poisoning from ammunition sources on raptor populations in Europe.

Poisoning caused by ingestion of spent lead (Pb) ammunition in food items is a common cause of death of raptors. However, there has been no previous attempt to assess the impact of lead poisoning on populations of raptors throughout Europe or examine how this relates to the prevalence of hunting. We used measurements of lead concentration in the liver from over 3000 raptors of 22 species found dead or dying in the wild in 13 countries and a lead poisoning threshold of 20 ppm (dry weight) to assess the proportion of these in which lead poisoning caused or contributed to death. The prevalence of lead poisoning as a cause of death of raptors varied substantially among European countries and was positively correlated across countries with the reported number of hunters per unit area. Ten species had a non-zero proportion of individuals with concentrations exceeding the lead poisoning threshold ranging between 0.3% and 16.5%. The estimated annual conditional death rate from lead poisoning for these ten species averaged 0.44% (range 0.06-0.85%). Scavenging species feeding regularly on carcasses of game animals,tended to have a high annual probability of death from lead poisoning. So too did some predators which only sometimes scavenge, but prey on frequently hunted birds, such as gamebirds, waterfowl and pigeons, which may contain ingested or embedded lead shot. Small-bodied predators had a low annual probability of death from lead poisoning. Modelling indicated that European populations of adult raptors of the ten focal species averaged 6.0% smaller (range 0.2-14.4%) than they would be without the effects of lead poisoning. A given rate of lead poisoning mortality resulted in greater expected population reductions for species with high annual survival rate and late age at first breeding.

Development of an Anti-Biofilm Screening Technique Leads to the Discovery of a Peptoid with Efficacy against Candida albicans.

Bacteria and fungi can secrete and reside within a complex polysaccharide matrix, forming a biofilm that protects these pathogens from the immune response and conventional antibiotics. Because many microbial pathogens grow within biofilms in clinical settings, there is a need for antimicrobial agents effective against biofilm-protected infections. We report the adaptation of a phenotypic high-throughput assay for discovering antimicrobial peptoids toward the screening of combinatorial libraries against established biofilms. This method, termed the Inverted Peptoid Library Agar Diffusion (iPLAD) assay, required optimization of growth media, reducing reagent, and fungal viability reporter. Once optimized, iPLAD was used to screen a combinatorial peptoid library against Candida albicans, a biofilm-forming fungal pathogen responsible for most hospital-acquired infections. This screening resulted in a lipopeptoid termed RMG9-11 with excellent activity against several species of Candida, including drug-resistant strains of C. albicans and the emerging and dangerous C. auris. Additionally, the cytotoxicity of RMG9-11 against several mammalian cell lines was minimal. This work provides a new method for the identification of compounds effective against biofilm-protected pathogens and demonstrates its utility by identifying a promising anti-Candida peptoid.

The effect of estrogen on brown adipose tissue activity in male rats.

OBJECTIVE: Centrally administered estrogen can increase sympathetic nerve activity to brown adipose tissue, resulting in thermogenesis. The central thermogenic effects of estrogen have not been investigated in males. Therefore, this study sought to investigate the effects of peripherally and centrally administered estrogen on thermogenesis, heart rate and mean arterial pressure in male rats. Thermogenesis was assessed by monitoring brown adipose tissue temperature. RESULTS: Peripherally administered estrogen elicited no significant effect on brown adipose tissue temperature, heart rate or mean arterial pressure. Centrally administered estrogen elicited a coincident increase in both brown adipose tissue and core temperature. Centrally administered estrogen also resulted in a decrease in mean arterial pressure but had no effect on heart rate. With the present data it is not possible to elucidate whether changes in temperature were the result of thermogenic or thermoregulatory mechanisms.

Fungal pathogens of cereal crops: Proteomic insights into fungal pathogenesis, host defense, and resistance.

Fungal infections of cereal crops pose a significant risk to global food security through reduced grain production and quality, as well as contamination of animal feed and human products for consumption. To combat fungal disease, we need to understand how the pathogen adapts and survives within the hostile environment of the host and how the host's defense response can be modulated for protection from disease. Such investigations offer insight into fungal pathogenesis, host immunity, the development of resistance, and mechanisms of action for currently-used control strategies. Mass spectrometry-based proteomics provides a technologically-advanced platform to define differences among fungal pathogens and their hosts at the protein level, supporting the discovery of proteins critical for disease, and uncovering novel host responses driving susceptibly or resistance of the host. In this Review, we explore the role of mass spectrometry-based proteomics in defining the intricate relationship between a pathogen and host during fungal disease of cereal crops with a focus on recent discoveries derived from the globally-devastating diseases of Fusarium head blight, Rice blast, and Powdery mildew. We highlight advances made for each of these diseases and discuss opportunities to extrapolate findings to further our fight against fungal pathogens on a global scale.

Common variable immunodeficiency disorders: What generalists should know.

Primary immune deficiency disorders (PIDDs) are common and underdiagnosed. Predominant antibody deficiencies (PADs) are the most common type of immune deficiency and comprise 55% of the immune deficiencies diagnosed.[1] Although immunoglobulin A (IgA) deficiency remains the most common type of PID, common variable immunodeficiency disorders remain the most common symptomatic PID for which medical therapy is sought.

EPOS 4 Patients.

EPOS2020 is the 4th and most recent version of the European Position Paper on Rhinosinusitis and Nasal Polyps which was first published in 2005. It aims to provide the most up to date scientifically robust information on the topic published in the literature which has been critically analysed by an international group of clinicians drawn from all disciplines dealing with these problems together with patients. The guidelines offer evidence-based recommendations and care pathways for acute and chronic rhinosinusitis in both adults and children. Management of these diseases from the patients' perspective is an important part of EPOS2020. Not only is this included in the main document but, for the first time, we have produced a separate supplement dedicated to and in collaboration with patients, EPOS4Patients, which aims to provide information in an accessible format, to answer frequently asked questions about these diseases and their treatment options as well as including useful patient resources and websites. It has never been more important for patients to be actively involved in their care. Being well informed helps you to make the best decisions together with your doctor.

Discovery and Characterization of a Rapidly Fungicidal and Minimally Toxic Peptoid against Cryptococcus neoformans.

A limited number of antifungals are available to treat infections caused by fungal pathogens such as Cryptococcus neoformans and Candida albicans. Current clinical antifungals are generally toxic, and increasing resistance to these therapies is being observed, necessitating new, effective, and safe antifungals. Peptoids, or N-substituted glycines, have shown promise as antimicrobial agents against bacteria, fungi, and parasites. Herein we report the discovery and characterization of an antifungal peptoid termed RMG8-8. This compound was originally discovered from a combinatorial peptoid library using the Peptoid Library Agar Diffusion assay to screen against C. albicans. Though the efficacy of RMG8-8 against C. albicans was modest (25 µg/mL), the efficacy against C. neoformans was excellent (1.56 µg/mL). Cytotoxicity against a panel of cell lines proved RMG8-8 to be minimally toxic, with selectivity ratios ranging from 34 to 121. Additional studies were carried out to determine the pharmacological importance of each peptoid monomer in RMG8-8, characterize the killing kinetics of this compound against C. neoformans (t 1/2 = 6.5 min), and evaluate plasma protein binding and proteolytic stability. Finally, a liposomal lysis assay suggested that RMG8-8 likely exerts fungal killing through membrane permeabilization, the generally accepted mechanism of action for most antimicrobial peptides and peptoids.

Investigating lipid headgroup composition within epithelial membranes: a systematic review.

Membrane lipid composition is often quoted within the literature, but with very little insight into how or why these compositions vary when compared to other biological membranes. One prominent area that lacks understanding in terms of rationale for lipid variability is the human gastro-intestinal tract (GIT). We have carried out a comprehensive systematic literature search to ascertain the key lipid components of epithelial membranes, with a particular focus on addressing the human GIT and to use compositional data to understand structural aspects of biological membranes. Both bacterial outer membranes and the human erythrocyte membrane were used as a comparison for the mammalian [epithelial] membranes and to understand variations in lipid presence. We show that phosphatidylcholine (PC) lipid types tend to dominate (33%) with phosphatidylethanolamines (PE) and cholesterol having very similar abundances (25 and 23% respectively). This systematic review presents a detailed insight into lipid headgroup composition and roles in various membrane types, with a summary of the distinction between the major lipid bilayer forming lipids and how peripheral lipids regulate charge and fluidity. The variety of lipids present in biological membranes is discussed and rationalised in terms function as well as cellular position.

A framework for automated gene selection in genomic applications.

PURPOSE: An efficient framework to identify disease-associated genes is needed to evaluate genomic data for both individuals with an unknown disease etiology and those undergoing genomic screening. Here, we propose a framework for gene selection used in genomic analyses, including applications limited to genes with strong or established evidence levels and applications including genes with less or emerging evidence of disease association. METHODS: We extracted genes with evidence for gene-disease association from the Human Gene Mutation Database, OMIM, and ClinVar to build a comprehensive gene list of 6,145 genes. Next, we applied stringent filters in conjunction with computationally curated evidence (DisGeNET) to create a restrictive list limited to 3,929 genes with stronger disease associations. RESULTS: When compared to manual gene curation efforts, including the Clinical Genome Resource, genes with strong or definitive disease associations are included in both gene lists at high percentages, while genes with limited evidence are largely removed. We further confirmed the utility of this approach in identifying pathogenic and likely pathogenic variants in 45 genomes. CONCLUSION: Our approach efficiently creates highly sensitive gene lists for genomic applications, while remaining dynamic and updatable, enabling time savings in genomic applications.

Parental access to hospitalised children during infectious disease pandemics such as COVID-19.

The COVID-19 pandemic has resulted in many hospitals severely limiting or denying parents access to their hospitalised children. This article provides guidance for hospital managers, healthcare staff, district-level managers and provincial managers on parental access to hospitalised children during a pandemic such as COVID-19. It: (i) summarises legal and ethical issues around parental visitation rights; (ii) highlights four guiding principles; (iii) provides 10 practical recommendations to facilitate safe parental access to hospitalised children; (iv) highlights additional considerations if the mother is COVID-19-positive; and (v) provides considerations for fathers. In summary, it is a child's right to have access to his or her parents during hospitalisation, and parents should have access to their hospitalised children; during an infectious disease pandemic such as COVID-19, there is a responsibility to ensure that parental visitation is implemented in a reasonable and safe manner. Separation should only occur in exceptional circumstances, e.g. if adequate in-hospital facilities do not exist to jointly accommodate the parent/caregiver and the newborn/infant/child. Both parents should be allowed access to hospitalised children, under strict infection prevention and control (IPC) measures and with implementation of non-pharmaceutical interventions (NPIs), including handwashing/sanitisation, face masks and physical distancing. Newborns/infants and their parents/caregivers have a reasonably high likelihood of having similar COVID-19 status, and should be managed as a dyad rather than as individuals. Every hospital should provide lodger/boarder facilities for mothers who are COVID-19-positive, COVID-19-negative or persons under investigation (PUI), separately, with stringent IPC measures and NPIs. If facilities are limited, breastfeeding mothers should be prioritised, in the following order: (i) COVID-19-negative; (ii) COVID-19 PUI; and (iii) COVID-19-positive. Breastfeeding, or breastmilk feeding, should be promoted, supported and protected, and skin-to-skin care of newborns with the mother/caregiver (with IPC measures) should be discussed and practised as far as possible. Surgical masks should be provided to all parents/caregivers and replaced daily throughout the hospital stay. Parents should be referred to social services and local community resources to ensure that multidisciplinary support is provided. Hospitals should develop individual-level policies and share these with staff and parents. Additionally, hospitals should ideally track the effect of parental visitation rights on hospital-based COVID-19 outbreaks, the mental health of hospitalised children, and their rate of recovery.

External carotid artery pseudoaneurysm following upper respiratory infection masquerading as a pharyngeal abscess in an 8-month-old.

Pseudoaneurysms are very rare with an incidence of less than 0.1% in the pediatric population. Approximately 30 cases of carotid artery aneurysms in children have been published in the literature, usually affecting children over one year of age. We present one of the youngest cases in the literature; the patient is an 8-month old female with a strep throat infection complicated by pseudoaneurysm development of the external carotid artery. Because of the rarity of these lesions, there is little known regarding the types of clinical presentation and management. They are commonly the result of direct arterial trauma; however, they can also occur secondary to infection, connective tissue disease or arteritis. We are presenting a case with a highly atypical presentation. When present, pseudoaneurysms harbor the potential risk of life-threatening hemorrhage and warrant immediate management. It is important to be aware of cases and the treatment modalities used to guide future diagnosis and planning.

COVID-19 outbreaks in care homes during the first wave: are Care Quality Commission ratings a good predictor of at-risk homes?

BACKGROUND: COVID-19 placed a significant burden on the care home population during the first wave. Care Quality Commission's care quality ratings are given to all English care homes and could be used to identify whether care homes are at risk of COVID-19 outbreaks. METHODS: An audit was performed, April 2020, of Liverpool care homes to identify associations between COVID-19 status and care quality ratings from the Care Quality Commission. Univariable logistic regression was performed to identify whether the Care Quality Commissions ratings were associated with a care home experiencing a COVID-19 outbreak, or a home having asymptomatic cases. FINDINGS: Over half of the care homes (53.2%, n=41), had laboratory-confirmed clinical cases and 39 (95.1%) of these were reported as outbreaks. A small number of care homes (10.4%, n=8) had asymptomatic cases and over a third had no clinical or asymptomatic cases (36.4%, n=28). There was no significant difference between the overall Care Quality Commission rating of Liverpool and English care homes (p=0.57). There was no significant association between any of the Care Quality Commission rating domains and the presence of COVID-19 outbreaks and/or asymptomatic cases. CONCLUSIONS: During the first wave of the COVID-19 pandemic, Care Quality Commission ratings were not associated with COVID-19 outbreaks or asymptomatic cases in care homes. Infection prevention and control components of Care Quality Commission ratings need to be strengthened to identify care homes at a potential risk of infectious disease outbreaks that may require targeted support. Further large-scale studies will be required to test the findings from this study.